X chromosome inactivation (XCI), the random transcriptional silencing of one X chromosome in somatic cells of female mammals, is a mechanism that ensures equal expression of X-linked genes in both sexes. XCI is initiated by Xist, a 17-kb non-coding RNA whose expression during early embryogenesis is both necessary and sufficient for silencing. Xist represses transcription in cis by coating only the X chromosome from which it is produced. Once Xist has been upregulated during early development or differentiation, it continues to be expressed from the inactive X (Xi) even in fully differentiated somatic cells. Prior to the initiation of XCI, Tsix, an antisense repressor of Xist, blocks Xist upregulation on the future active X chromosome (Xa).
An understanding of the factors and mechanisms involved in XCI is directly relevant to certain human diseases (e.g., dominant X-linked diseases). For example, loss-of-function mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene lead to the neurodevelopmental disorder Rett syndrome (RTT). Most RTT patients are females who are heterozygous for MECP2 deficiency due to random XCI. Therapeutic options for the treatment of dominant X-linked diseases, such as Rett syndrome, remain limited. Accordingly, there is a need for new compositions and methods of treatment for dominant X-linked diseases.